Field of the Invention.
The present invention relates to a drug for treating and/or preventing a respiratory disease, particularly, cough, comprising a compound represented by formula (I) described later, a salt, or a hydrate thereof. The present invention further relates to a method for treating and/or preventing a respiratory disease, particularly, cough, comprising administering the compound described above or the like.
Description of the Related Art.
Cough is a common defensive reflex action in the respiratory tract for healthy subject, however, persistent cough associated with various diseases greatly reduces patients' quality of life.
Antitussives are classified into central antitussives, which exhibit antitussive activities by blocking the cough center, and peripheral antitussives, which block stimulation of peripheral cough receptors. Central antitussives, such as codeine phosphate and dextromethorphan, cause adverse drug reactions including respiratory depression, sleepiness, constipation, and the like and also present problems such as resistance and dependence due to repeated use. On the other hand, the peripheral antitussives, such as methylephedrine, often have insufficient antitussive activities. For such reasons, there has been a demand for the development of safe and more effective antitussives.
Voltage-gated sodium channels (Nays) are ion channels each including an α subunit having four domains and auxiliary acting β subunits, at least nine subtypes thereof having been reported so far, and these subtypes respectively have different expression distributions and physiological actions so as to regulate biological functions.
The sodium channels are an intrinsic part of neural activities, and drugs such as lidocaine and mexiletine are known as inhibitors for sodium channels. As for cough, the respiratory tract is considered to be controlled by various neural activities. There are many preclinical and clinical data showing that these sodium channel inhibitors are effective for the suppression of cough (Patent Literatures 1 and 2 and Non-Patent Literatures 1 and 2). Such drugs have, however, low selectivity for the Nav subtypes. Since sodium channels of the different subtypes are expressed in muscles, cardiac muscle cells and the central nervous system as shown in Table 1, the problem arises of adverse drug reactions caused when such drugs are systemically administered.
TABLE 1SubtypeMain expression siteNav1.1Central nervous systemNav1.2Central nervous systemNav1.3Central nervous systemNav1.4Skeletal muscleNav1.5Cardiac muscle cellsNav1.6Sensory/motor nervous systemNav1.7Sensory nervous systemNav1.8Sensory nervous systemNav1.9Sensory nervous system
Patent Literature 1 relates to a Nav 1.7 modulator and states that the Nav 1.7 modulator is useful for various respiratory diseases. This patent literature specifically describes a compound represented by formula (A) below (for example, Example 6), which is described in the claims as falling within a structure represented by formula (B) below. A feature of the compound described in said patent literature is that the compound is a pyridine derivative substituted at the 2-position by a piperidine ring or a pyrrolidine ring. By contrast, the compound used in the present invention is very different therefrom, for example, in that a cycloalkane is connected to an aromatic ring through an oxygen atom. Patent Literature 1 neither describes nor suggests the structure of the compound used in the present invention.

Patent Literature 2 below relates to a Nav 1.7 modulator and states that the Nav 1.7 modulator is useful for various respiratory diseases. This patent literature specifically describes a compound represented by formula (C) below (for example, Example 474), which is described in the claims as falling within a structure represented by formula (D) below. A feature of the compound described in said patent literature is that the compound is a pyridine derivative substituted at the 2-position by a piperazine ring. By contrast, the compound used in the present invention is very different therefrom, for example, in that a cycloalkane is connected to an aromatic ring through an oxygen atom. Patent Literature 2 neither describes nor suggests the structure of the compound used in the present invention.

Patent Literature 3 below relates to a Nav 1.7 modulator and specifically describes, for example, a compound represented by formula (E) below (for example, Example 811). Features of the compound described in this patent literature are that two aromatic rings are connected through an oxygen atom, and further, N-substituted sulfonamide is connected to one of the aromatic rings (phenyl group). The compound used in the present invention differs therefrom in that a cycloalkane is connected to an aromatic ring through an oxygen atom. Patent Literature 3 neither describes nor suggests the structure of the compound used in the present invention.

The compound disclosed in said Patent Literature 3 is described in the claims as falling within a structure represented by formula (F) below. The moiety B in this structure is defined as “phenyl or Het2, wherein Het2 is defined as a 5- or 6-membered aromatic heterocyclic group containing (a) one to four nitrogen atoms, (b) one oxygen atom or one sulfur atom, or (c) one oxygen atom or one sulfur atom and one or two nitrogen atoms”. Thus, the moiety B is an aromatic substituent, and the patent reference does not disclose that this moiety is a saturated substituent. Specifically, said patent literature does not disclose that a cycloalkane can be introduced as the corresponding partial structure, as in the compound of formula (I) used in the present application. The patent literature does not disclose that the Nav 1.7 modulator is effective for respiratory diseases.

Patent Literature 4 below relates to an N-type calcium channel inhibitor and specifically describes, for example, a compound represented by formula (G) below (for example, Example 5(11)). The compound described in said patent reference has a structure in which an aromatic ring and a saturated heterocyclic ring are connected through a polymethylene(oxy) chain. An N-substituted sulfonamide is bonded to an aromatic ring (phenyl group), and two substituents are further introduced at the nitrogen atom of this sulfonamide. Specifically, a feature of this compound is that the nitrogen atom of the sulfonamide is di-substituted. The compound of the present invention differs therefrom in that: the saturated ring is not a heterocyclic ring; a cycloalkane and an aromatic ring are connected through an oxygen atom and not through a polymethylene chain; and the sulfonamide moiety is mono-substituted at its nitrogen atom. Said Patent Literature 2 neither describes nor suggests at all the structure of the compound used in the present invention. The patent literature does not disclose that the Nav 1.7 modulator is effective for respiratory diseases.

Neither does the compound used in the present invention fall within a structure represented by formula (H) below described in the claims of Patent Literature 4, nor is the structure of the compound used in the present invention suggested by the description related to this structure.
